Role of Aldosterone and Adiponectin in Inter-Tissue Communication in Diastolic He

描述（由申请人提供）：舒张性心力衰竭（HF），也被称为“心力衰竭保留射血分数”，占所有HF表现的50%，但与收缩期心力衰竭不同，尽管发病率和死亡率增加，治疗仍然无效。这部分源于缺乏对舒张期心衰的机制理解。高血压是舒张期心衰的主要原因，预计随着高血压发病率的上升，舒张期心衰的患病率也会增加。肥胖者血压控制不佳和舒张期心衰的发生率也很高。这增加了由fa分泌的因子可能在高血压相关舒张性心衰中起作用的可能性。尽管醛固酮与动脉高血压之间存在因果关系，但越来越多的证据表明醛固酮与肥胖之间存在联系，有证据表明，脂肪细胞除了分泌脂联素（APN）外，还可能释放独立于血管紧张素- ii的分泌因子，刺激醛固酮释放。APN是一种脂肪来源的血浆蛋白，通过调节心血管细胞的磷酸化信号发挥抗炎和抗肥厚作用，并与高血压和收缩期心力衰竭的发生有关。APN水平在肥胖和高血压中降低，但在收缩期HF（也称为“心力衰竭-射血分数降低”）中升高。相反，醛固酮在肥胖、高血压和心衰患者中升高。最近我们的实验室发现，高血压引起的舒张期心衰患者低脂联素血症加重左室肥厚、舒张功能障碍和舒张期心衰。我们试图检查APN对舒张期心衰中醛固酮相对升高的贡献。这一提议的主要目的是醛固酮和APN之间的失调有助于舒张性心衰和不良心脏重构的发病机制。据我们所知，这个概念模型还没有经过检验或假设。我们将检验APN水平的改变促进醛固酮增加的假设，增加舒张期心衰和舒张功能障碍的倾向。为了验证这一假设，我们将测试以下目标：

DESCRIPTION (provided by applicant): Diastolic heart failure (HF), also known as "heart failure-preserved-ejection fraction", accounts for up to 50% of all HF presentations, but unlike systolic HF, therapies remain ineffective despite increasing morbidity and mortality. This stems, in part, from a lack of mechanistic understanding about diastolic HF. Hypertension is the major cause of diastolic HF and the prevalence of diastolic HF is projected to increase as the incidence of hypertension rises. Obese individuals also have a high incidence of poorly controlled blood pressure and diastolic HF. This raises the possibility that factors secreted by fa may play a role in hypertension-related diastolic HF. Although a causal link exists between aldosterone and arterial hypertension, increasing evidence demonstrates a link between aldosterone and obesity with evidence that adipocytes, in addition to secreting adiponectin (APN), may release secreted factors that stimulate aldosterone release independent of angiotensin-II. APN, an adipose-derived plasma protein, exerts anti-inflammatory and anti-hypertrophic effects by modulating phosphorylation signals in cardiovascular cells and is implicated in the development of hypertension and systolic HF. APN levels are decreased in obesity and hypertension, but elevated in systolic HF, also known as "heart failure-reduced-ejection fraction". Conversely aldosterone is increased in obesity, hypertension and in HF. Recently our lab showed that hypoadiponectinemia in hypertension-induced diastolic HF exacerbates left ventricular hypertrophy, diastolic dysfunction and diastolic HF. We seek to examine the contribution of APN to the relative increase in aldosterone in diastolic HF. The broad objective of this proposal is that dysregulation between aldosterone and APN contributes to the pathogenesis of diastolic HF and adverse cardiac remodeling. To our knowledge this conceptual model has not been tested nor hypothesized. We will test the hypothesis that an alteration in APN levels facilitates an increase in aldosterone increasing the propensity to diastolic HF and diastolic dysfunction. To address this hypothesis we will test the following aims: Aim 1) to investigate if dysregulation of APN levels are associated with alterations in aldosterone levels in human diastolic HF. Hypothesis 1. Aldosterone and APN levels are elevated in stable diastolic HF patients and are associated with left ventricular (LV) diastolic dysfunction measurements. Hypothesis 2. Changes in aldosterone and APN levels (between acutely, decompensated and stable, ambulatory diastolic HF) are associated with disease progression (as determined by echocardiographic derived measures of LV diastolic dysfunction) in diastolic HF. Aim 2) To determine if APN ameliorates the transition from hypertension to diastolic dysfunction and diastolic HF in a mouse model of diastolic HF and dysfunction. Aim 3) To investigate the role of autophagy in diastolic dysfunction in cardiac myocytes and the signaling mechanisms involved in cell-to-cell communication between cardiac myocytes and adipocytes in diastolic HF.